Activity patterns in the brain establish the manner in which sensory information is perceived and salience is assigned. Disruptions of these patterns are likely a major cause of mental illness. The dopamine neurons of the ventral tegmental area and substantia nigra pars compacta, locat- ed within the ventral mesencephalon, encode perhaps one of the most important signals for re- inforcement learning in the brain: reward prediction error. This signal is encoded by the firing pattern of dopamine neurons, which controls the release of dopamine at target regions. Specifi- cally, transient, impulse-dependent release of dopamine, driven by bursts of action potentials, is critical for natural processing in the brain. Just as critical, pauses in dopamine cell activity have opposite psychological meaning for reward information coding and are thought to signal the ab- sence of an expected reward. In vitro studies have determined that ion channels drive the firing patterns of dopamine neurons. Also, the multitude of physiological consequences of their open- ing and closing makes ion channels and their associated receptors highly compelling as impor- tant therapeutic targets for treating many of the symptoms of mental illnesses. However, de- spite their importance virtually nothing is known of the impact of specific ion channels on dopamine firing pattern during behavior. Identification of the ion channels responsible for bursts and pauses is a key step in understanding the mechanism of reinforcement learning, but has so far proven elusive. This is largely due to the difficulty in obtaining intracellular whole- cell recordings of dopamine neurons in awake, behaving animals. A method to routinely obtain in vivo whole-cell recordings from identified dopamine neurons in mice has been developed in our lab. For this R21 ?Exploratory/Developmental Research Grant Award? to ?support devel- opment of novel techniques? further success in obtaining whole-cell recordings in awake behav- ing mice will be developed to determine the underlying conductances that drive dopamine neu- rons to burst and pause during reward-related behavior.